In the blink of an eye, the COVID-19 pandemic has been raging on the planet for two years.
According to data released by the World Health Organization (WHO), as of January 26, more than 352 million confirmed COVID-19 cases and more than 5.6 million deaths worldwide [1].
With the emergence of the Omicron mutation strain at the end of 2021, the number of new confirmed cases in the Western world has reached a new high, and more and more people have begun to believe that the new crown may coexist with humans.
That being the case, it may be necessary to take a closer look at COVID-19.
It is the seventh type of coronavirus that can infect the human body!
Looking back at the beginning of the outbreak of the new crown epidemic in 2019, some doctors quickly associated with SARS, not only because the patient's symptoms are very similar to SARS, but also because the new crown and SARS look very similar, after all, they are all coronaviruses.
The coronavirus gets its name from its shape, and under electron microscopy, the coronavirus looks very much like a crown. We now know that coronaviruses are single-stranded positive-stranded RNA viruses with a genome size of about 26 to 32 kb[2]. In addition, of all known RNA viruses, the genome of the coronavirus is the largest [2].
Electron microscopy picture of the new crown virus (Source: NIAID-RML)
In fact, the history of the coronavirus is not very long, and in 1966, scientists first discovered the coronavirus that can infect humans, which is HCoV-229E isolated from the respiratory tract of common cold patients [2]. A year later, another team isolated the coronavirus HCoV-OC43 from the respiratory tract of common cold patients [2].
For more than three decades for the remainder of the twentieth century, no new coronaviruses were detected that infected humans until sars-CoV appeared in 2002. Sars-CoV must be familiar to everyone, its 9% case fatality rate [2], still makes people feel uneasy, fortunately, in 2003, it disappeared from the human world.
HCoV-NL63 was discovered in 2004 and HCoV-HKU1 was discovered in 2005. Fortunately, both coronaviruses are similar to HCoV-229E and HCoV-OC43 and both are milder. According to statistics, about 10-30% of upper respiratory tract infections are caused by these four coronaviruses each year, and patients generally have milder symptoms [3].
In June 2012, a 60-year-old Saudi Arabian man developed symptoms such as fever, cough, sputum production, and shortness of breath before dying of severe pneumonia and multiple organ failure. It wasn't until October of that year that the New England Journal of Medicine published the real cause of the man's death—contracting a new type of coronavirus, later known as MERS-CoV.
Compared to the previous five coronaviruses, MERS-CoV is an out-and-out "big devil". According to statistics, as of December 31, 2015, there were 1621 confirmed MERS-CoV cases worldwide, with 584 deaths, and the case fatality rate was as high as 36% [2]. Fortunately, MERS-CoV has not spread globally.
However, compared to the coronavirus (SARS-CoV-2) that emerged at the end of 2019, the "big devil" of MERS-CoV is also dwarfed. Although the fatality rate of new coronavirus infection is far less than that of MERS-CoV, the number of deaths caused by new coronavirus and the far-reaching impact on human society are far less than THAT of MERS-CoV.
It is not difficult to see from the name that the new crown virus is very similar to SARS-CoV, in fact, nearly 80% of the 30kb genome of the new coronavirus is homologous to SARS-CoV [3]. Structurally, like six other coronaviruses, the virion consists of a nucleocapsid (N), membrane (M), envelope (E), and spike (S) proteins, as well as a viral genome [5].
Schematic diagram of coronavirus structure[5]
However, there are certain differences in the way the coronavirus enters the cell. For example, CORONAVIRUS, SARS-CoV, and HCoV-NL63 utilize angiotensin-converting enzyme 2 (ACE2), HCoV-229E utilizes aminopeptidase N (ANPEP), and MERS-CoV uses dipeptidase 4 (DPP4) to enter cells [6-9]. Of course, without these receptors, coronaviruses can also enter cells, but the efficiency will be greatly reduced.
The process by which the new coronavirus infects human cells
It is well known that the process by which a virus infects a cell can be divided into five steps: adsorption, release of genetic material, replication proliferation, assembly, and release of virions. Among them, the first step of adsorption is the top priority, and it is also one of the important targets of vaccines and antiviral drugs.
At the beginning of the outbreak of the new crown epidemic, mainland scientists were the first to find that the new crown virus infected human cells depends on the binding of the virus S protein receptor binding region (RBD) to the ACE2 on the host cell [7-9]. It can be seen that S protein and ACE2 are the keys to successful virus adsorption.
Scientists have found that the S protein of the new coronavirus consists of two non-covalently bound subunits S1 and S2, of which the S1 subunit binds to ACE2, and the S2 subunit anchors the new coronavirus to the membrane and mediates the fusion of the virus with the cell membrane.
The specific process is roughly that the RBD in the S1 subunit binds to ACE2, resulting in a change in the conformation of the S protein, while the S2 subunit is exposed, the transmembrane serine protease 2 (TMPRSS2) on the surface of the human cell cuts the S2' site on the S2 subunit, and the fusion peptide (FP) in the S2 subunit is exposed, initiating fusion pore formation [5]. In this way, the new crown virus has completed the adsorption step. Subsequently, the genetic material of the new crown virus enters the human cell through the fusion hole, opening the process of replication proliferation, assembly and release of the virus.
The main route of the new crown virus into the cell[5]
Once the new crown virus has successfully entered the cells of the human body and completed the series of processes described above, the infection really begins.
On March 20, 2020, in order to standardize the diagnosis and treatment of COVID-19, Mandeep R. Mehra and Hasan K. Siddiqi of The Bregan and Women's Hospital of Harvard Medical School pioneered a clinical staging system for COVID-19 [10].
They divided the physiological process of COVID-19 into three stages: stage I (mild), early infection; stage II (moderate), lung involvement; and stage III (severe), systemic excessive inflammation. Next, we will understand these three stages one by one.
Let's start with stage I (mild) – early infection.
At this stage, the new crown virus has just infected the host, and the main task is to reproduce and settle in the host, and it is mainly concentrated in the respiratory system. For most people, this phase is actually an incubation period, with mild and non-specific symptoms such as malaise, fever, and dry cough [10,11].
Mehra et al. argue that at this stage, if effective antiviral therapy is used, it is possible to reduce the duration of symptoms, minimize infectivity, and prevent the progression of severity. If the virus is controlled at this stage, the prognosis and recovery of the patient will be very good [10,11].
Consider stage II (moderate) – lung involvement.
At this stage, the proliferation of the new crown virus and local inflammation of the lungs are the norm, and patients will develop viral pneumonia with cough, fever, and possibly lack of oxygen. Chest X-ray or CT scan may reveal bilateral infiltrates or terrazzo in the lungs. Blood tests may reveal lymphopenia and increased transaminases. In addition, markers of systemic inflammation in infected people may be elevated, although not significant. Treatment at this stage consists mainly of supportive measures and antiviral therapy [10,11].
Finally, stage III (severe) – systemic hyperinflammation.
This is the most severe stage of COVID-19, and fortunately, only a small number of patients will progress to this stage. At this stage, the number of auxiliary, inhibitory and regulatory T cells in the patient's body decreases, and the levels of inflammatory cytokines and biomarkers such as IL-2, IL-6, IL-7, granulocyte colony stimulator, macrophage inflammatory protein 1-α, tumor necrosis factor-α, C-reactive protein, ferritin and D-dimer are significantly increased. Therefore, the most obvious feature of patients at this stage is systemic hyperinflammation. Treatment at this stage relies primarily on immunomodulatory drugs [10,11].
Clinical staging system[11]
From the clinical staging divided by Mehra et al. and their interpretation of clinical staging, it is not difficult to see that the use of antiviral therapy may allow infected people to obtain the greatest benefit when the physiology of the new crown pneumonia is in stageS I and II, that is, in the mild to moderate stages.
In fact, a large number of clinical studies of neutralizing antibodies have confirmed that for adult COVID-19 patients who are symptomatic, non-hospitalized, and have a risk factor for developing severe disease, neutralizing antibodies can significantly reduce the risk of hospitalization and death [12-15]. Among them, the combination of amphavir monoclonal antibody/romizumab independently developed by the mainland can reduce the risk of hospitalization and death due to disease progression in the above patient groups by 80% (P<0.00001) [16].
These data confirm that early antiviral therapy can indeed benefit patients.
How do human immune cells fight the coronavirus?
After understanding the process of new crown virus infection, everyone should also want to know how the human immune system responds to the infection of new crown virus.
We all know that there are two types of immune responses in the human body, one is congenital immunity and the other is acquired immunity. The first response to COVID-19 infection was the innate immune response.
Once the new coronavirus infects human cells, it is recognized by pattern recognition receptors such as Toll-like receptors (TLR) 3, 7, 8 and 9, as well as the viral infection receptors RIG-I and MDA5, which activate the type I interferon (IFN) response program and IFN-stimulated genes. Moreover, TLR3 also promotes activation of NLRP3 inflammasomes, induces caspase-1-dependent lysis, and releases of the key pro-inflammatory cytokines interleukin 1β (IL-1β) and IL-18, which in turn triggers gasdermin D-mediated cytofoulatory [17]. In this way, the proliferation of the new crown virus is suppressed by the death of infected cells.
Innate immune response processes[17]
The rate of acquired immune responses is also not slow. When the new coronavirus enters the cell, the virus-specific protein is presented to cytotoxic T cells by the Class I major histocompatibility complex (MHC) protein. Cytotoxic T cells are activated, begin to divide and clonally dilate, and differentiate virus-specific effects and memory T cells [18]. Virus-specific effector T cells lyse virus-infected cells and prevent the virus from replicating and proliferating.
At about the same time, antigen-presenting cells such as dendritic cells and macrophages present viral peptides to CD4+ T cells through class II MHC, prompting them to differentiate into cells such as type 1 helper (Th1) T cells. B cells can also directly recognize viruses and be activated by viruses [18]. Activated B cells proliferate rapidly and turn on somatic supermutation (SHM), where genes encoding neutralizing antibody variables will begin to mutate at a rate much faster than other cells to evolve plasma cells (PC, antibody-secreting cells) that synthesize antibodies with stronger affinity with viral antigens. Subsequently, helper T cells help screen plasma cells and have achieved affinity maturation of neutralizing antibodies [19].
Acquired immune response processes[18]
In the acquired immune response, it is worth mentioning the somatic supermutation (SHM) of B cells. After several rounds of somatic hypermutations, B cells can synthesize countless neutralizing antibodies, but the neutralizing activities of these neutralizing antibodies are not the same, some are stronger, some are weaker.
At present, the neutralizing antibodies used in clinical practice are basically screened from the plasma neutralizing antibodies of a large number of recovered patients. For example, Tengsheng Huachuang screened a pair of neutralizing antibodies with strong binding ability and complementary to RBD from more than 200 human-specific monoclonal antibodies[20], and obtained the approved ampaviumab/romizumab monoclonal antibody after Fc segment modification.
Coronavirus mutation – Evading the surveillance of the body's immune system
As the saying goes, where there is oppression, there is resistance. Since human immunity, as well as neutralizing antibodies, put enormous pressure on the coronavirus, they can also mutate. This is especially true for coronaviruses with single-stranded RNA.
Studies have shown that the S protein of the new coronavirus evolves at about 10 times faster than the influenza virus hemagglutinin (HA), which is an unprecedented rate of evolution [21]. No wonder so many new variants of covid-19 have emerged in just two years that have strained humanity.
To facilitate the monitoring and research of new variants of the new coronavirus, the WHO divides them into three categories: strains of concern (VOCs), strains of concern (VOIs), and strains under surveillance (VUM).
VoCs pose the greatest threat to humans, with the WHO identifying five VOCs so far: Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529). Every new VOC birth replaces the previous one and leads to a pandemic.
Today, Omicron, which has more than 30 mutations in the S protein and has caused vaccine failure and decreased activity of partially neutral antibodies[23], has replaced Delta as the dominant strain in the Western epidemic.
From recent clinical studies, patients infected with the Omicron strain appear to have less clinical manifestations and reduced hospitalization and mortality [24,25]. Studies have shown that this may be related to vaccination on the one hand [26] and to a decrease in the ability of TMPRSS2 to cleave spike proteins in the Omicron mutant strain on the other [27]. However, the stronger transmissibility of Omicron strains [28,29], increased risk to high-risk populations, and short-term large-scale population infection can still cause a medical run, leading to a rapid increase in the overall number of severe cases and deaths.
The good news is that in the past month or two, scientists have found at least three protocols to deal with the Omicron variant.
The first is a vaccine booster injection (third dose). Studies have found that although two doses of the COVID-19 vaccine are difficult to protect against the Omicron variant, after receiving the mRNA vaccine [30] or the inactivated vaccine booster needle [31], the activity of the vaccinated serum antibody against the Omicron variant is restored, but it is still lower than that of the wild strain.
The second response is to bind to a neutralizing antibody at a specific site. Although the activity of most neutralizing antibodies has decreased[23], studies have shown that the activity of neutralizing antibodies (Sotrovimab and romimab) that binds to the S protein RBD site IV is virtually unaffected by the Omicron strain mutation site [32]. This is one of the reasons why the ampavirinumab/romizumab combination maintains neutral activity on the Omicron variant strain.
The third response weapon is small molecule drugs. Studies in multiple laboratories have shown that the three small molecule drugs that have been approved by the FDA for emergency use remain unchanged for all current VOC activity [33,34].
With this "three-plate axe", the war between mankind and the new crown virus is not completely invincible.
In general, with the deepening of scientists' understanding of the new crown virus and new crown pneumonia, we can gradually understand the weaknesses of the new crown virus, and finally have a high probability of finding a breakthrough to defeat the enemy. Perhaps soon humanity will be able to "live peacefully" with the coronavirus.
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The author of this article 丨BioTalker